vitamin d, infections and immune-mediated diseases · future science group 91 vitamin d,...

89ISSN 1758-427210.2217/17584272.4.1.89 © 2009 Future Medicine Ltd Int. J. Clin. Rheumatol. (2009) 4(1), 89–103

REVIEW

Vitamin D, infections and immune-mediated diseases

Vitamin D has been an exciting fi eld of research in recent years, with more than 1400 publications published on the subject in 2008. The lay press has published articles, the internet is full of information and pharmacies have prominent displays of vitamin D supplements. Historically, vitamin D has been thought only to have an effect on calcium metabolism and bone. Vitamin D defi ciency was thought only to cause rickets or osteomalacia. Recent work has found that vitamin D affects many other cells and tissues. Basic science, epidemiological, case–control and cohort studies have been conducted that show an effect of vitamin D on infections and autoimmune diseases such as multiple sclerosis, infl ammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus and Type 1 diabetes. Further research is needed in each of these areas to elucidate the mechanism vitamin D uses to affect the immune system and to develop prevention and/or treatment guidelines.

KEYWORDS: 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D, autoimmune, immunity, infection, vitamin D

Laura AG ArmasCreighton University, Osteoporosis Research Center, 601 North 30th Street, Suite 4820, Omaha, NE 6813, USATel.: +1 402 280 4470Fax: +1 402 280 [email protected]

Defi nition & prevalence of vitamin D defi ciencyThe defi nition of vitamin D defi ciency has been controversial, but most experts would agree that a 25-hydroxyvitamin D (25(OH)D) level of less than 20 ng/ml is defi cient, and that more than 30 ng/ml would be a better level based on calcium homeostasis end points such as para-thyroid hormone suppression [1–3] and maximum calcium absorption [4].

Depending on which defi nition is used, the prevalence is high among several different popu-lations. At one time, we thought the risk was only in the elderly and in those living in nursing homes, but we have seen that the elderly living in the com-munity, as well as children and younger adults, are also at risk of defi ciency. For example, approxi-mately 50% of young people of all races living at a northern latitude were considered to be vitamin D defi cient [5,6]. In another study, 32% of young indoor workers were vitamin D defi cient, despite drinking milk and taking multivitamins [7]. There also appears to be a risk even in sunny areas if people are indoors or skin is extensively covered. Studies in Saudi Arabia, Australia, Turkey, India and southern Florida have found that 30–50% of children and adults are vitamin D defi cient [8,9].

This high prevalence of vitamin D defi ciency is especially worrisome when we consider new research that links low vitamin D status with increased risks of several illnesses, including can-cer, autoimmune disorders and cardio vascular disease [10].

History of vitamin D discoveryThe history of vitamin D discovery began in the early 19th century with the discovery that sun exposure, cod liver oil and, subse-quently, artifi cial ultraviolet light cured rickets [11]. The chemical structure of vitamin D was determined in 1936 and it was shown that cod liver oil contained the same chemical. In 1971, it was established that vitamin D undergoes hydroxylation in the liver and subsequently the kidney. In 1975, the vitamin D receptor was discovered and shortly after, it was located in most tissues and cells throughout the body [12]. This leads us to the present (and future) dis-covery of what vitamin D is doing in all these different tissues.

Vitamin D pathophysiologyVitamin D is formed in the epidermis, and to a small extent in the dermis, when UV-B light (290–315 nm wavelength) strikes 7-dehydro-cholesterol generating previtamin D

3. The

warmth of the skin converts the previtamin D3

to native vitamin D3. Native vitamin D

3 is trans-

ferred to the circulation, where it is carried by vitamin-D-binding protein [13].

Native vitamin D can also be obtained in oral form as D

2 (from irradiated yeast) or D

3 (from

irradiated 7-dehydrocholesterol derived from lanolin). Dietary forms of native vitamin D are absorbed in the proximal small bowel and trans-ported through the lymphatic system bound to chylomicrons [13].

Int. J. Clin. Rheumatol. (2009) 4(1)90 future science group

REVIEW Armas

Native vitamin D (of either form) is car-ried by vitamin-D-binding protein to the liver, where it is hydroxylated to form 25(OH)D. This is the major circulating form that is measured to assess vitamin D status. 25(OH)D is further hydroxylated either by the kid-ney to produce 1,25-dihydroxyvitamin D (1,25(OH)

2D) for systemic use or by individual

cells for internal cell regulation (see below for more detail on intracellular production and use of 1,25[OH]

2D). Although 1,25(OH)

2D

is classically considered the active form of vita-min D, its systemic level is highly regulated by calcium homeostasis signals, so it does not indi-cate overall vitamin D status. In fact, because of this tight regulation, serum 1,25(OH)

2D

levels can be normal or elevated in the face of vitamin D defi ciency. For details on vitamin D nomenclature, see BOX 1.

Like other steroid hormones, 1,25(OH)2D

acts on a nuclear receptor. It is taken up by the cell and transported to the nucleus where it binds to a vitamin D receptor (VDR). This complexes with a retinoic acid X receptor, which then binds to vitamin D response elements in the genome and modifi es over 200 genes. This interaction regulates gene transcription of a variety of fac-tors. Many of these factors are involved, not sur-prisingly, with calcium homeostasis and bone remodeling. The vitamin D response elements also modify genes responsible for cell regula-tion, including proliferation, differentiation and apoptosis. The VDR is present in most tissues and organs in the body and it has been known for 30 years that 1,25(OH)

2D localizes to

many tissues and organs. The immune cells, T and B lymphocytes, neutrophils, macrophages and dendritic cells all contain a VDR. When this was fi rst discovered, 1,25(OH)

2D looked

promising as a treatment targeting the VDR, but this direct approach was limited by severe hypercalcemia.

Mechanism of vitamin D in the immune systemThe disparate effects of vitamin D on everything from diabetes to seasonal affective disorder to protection from infectious diseases and cancer seem on the surface to be unrelated, but a recent series of experiments demonstrate the mechanism vitamin D uses in the immune system, and also provide hints of the role that vitamin D plays in other cells. The key to the wide-reaching effects of vitamin D is the intracellular 1-α-hydroxylase that is located in cells throughout the body. The exact role that vitamin D plays in every cell has not yet been elucidated, but investigators are working on possible mechanisms. There are two main outcomes of vitamin D on immunity: increased immunity against antigens and modula-tion of the autoimmune response. These actions of vitamin D are accomplished through a variety of mechanisms. Below is a basic explanation of the mechanisms as far as we understand them today.

Increased immunity against antigens The mechanism for increased immunity against antigens has been elegantly explained by Liu and colleagues [14] (see FIGURE 1). It was known for several years that many cells contain a 1-α-hydroxylase enzyme, but the purpose was unclear until a series of experiments in human macrophages showed that 25(OH)D is converted intracellularly to 1,25(OH)

2D in response to the interaction of a

Toll-like receptor with a bacterial antigen. This interaction activates the expression of genes for 1-α-hydroxylase and cathelicidin. This leads to an elevated production of cathelicidin, a bactericidal peptide, but only in the presence of 25(OH)D or 1,25(OH)

2D. Cathelicidin is effective not only

against bacteria, but also viruses [15] such as herpes simplex [16] and infl uenza [17]. Vitamin D could be used in either of two forms: 1,25(OH)

2D

could be used by the cell directly, or 25(OH)D could be converted to 1,25(OH)

2D intra cellularly

and then used. In this work, they also showed a dose–response effect of 25(OH)D in human serum. Serum containing higher levels of 25(OH)D (mean: 78 nmol/l) versus serum with lower 25(OH)D levels (mean: 22 nmol/l) increased cathelicidin gene expression by twofold. This explains the use of circulating 25(OH)D to pro-duce 1,25(OH)

2D intracellularly, so the person is

not at risk of hypercalcemia from high systemic levels of 1,25(OH)

2D. When this intracellular

mechanism is activated, the enzyme responsi-ble for catabolism of 1,25(OH)

2D is also acti-

vated, keeping the 1,25(OH)2D production and

Box 1. Glossary of vitamin D nomenclature.

Native vitamin D: vitamin D before it is hydroxylated by the liver. It can be obtained through skin production or vitamin D supplements.25-hydroxyvitamin D (25[OH]D): vitamin D after it is hydroxylated by the liver. This is the lab measurement that indicates vitamin D status.1,25-dihydroxyvitamin D (1,25[OH] 2D): vitamin D after it is hydroxylated by both the kidney and the liver. This can be obtained in oral or intravenous forms for use in renal patients and for clinical trials.Vitamin D analogs: several different forms of 1,25[OH] 2D that have been modifi ed or synthesized to avoid the hypercalcemic effects of 1,25[OH]2D.

www.futuremedicine.com 91future science group

Vitamin D, infections and immune-mediated diseases REVIEW

cata bolism completely self contained. This mech-anism not only explains the role of vitamin D in macrophages specifi cally, but also explains the role that vitamin D is likely to play in other types of cells. It is probable that other cells are activated by a stimulus (e.g., antigen), and in the presence of adequate 25(OH)D, express genes specifi c to that cell’s function (e.g., T cells and cytokines).

Modulation of the immune responseWith the above intracellular 1-α-hydroxylase in mind, the effect of vitamin D on autoimmune disease occurs through several mechanisms, each specifi c to the cell it is targeting. Vitamin D acts both directly and indirectly on several immune cells, including B and T lymphocytes, dendritic cells and macrophages (see FIGURE 2).

LymphocytesThe T lymphocytes (T cells) are central players in autoimmune disease. They respond to antigens on or inside cells, such as tumor cells or viruses.

When stimulated by these antigens, the T cells produce the inflammatory cytokines IFN-γ, IL-2 and TNF-α. There are two types of helper T cells, Th1 and Th2. Th2 cells are important for antibody-mediated immunity, while Th1 cells can react against ‘self ’ proteins causing autoim-mune diseases such as Type 1 diabetes (T1D), inflammatory bowel disease (IBD), multiple sclerosis (MS) and rheumatoid arthritis (RA). 1,25(OH)

2D directly inhibits the proliferation of

Th1 cells and decreases their cytokine production [18]. In murine models, if vitamin D is defi cient or the VDR is absent, Th1 actions are more promi-nent [19,20]. In vitro, treatment with 1,25(OH)

2D

inhibits the production of Th1 cells and promotes Th2 cell development [18,21]. The overall effect of T cells is to increase self-tolerance [22].

B lymphocytes (B cells) are also affected by vitamin D. Cell cultures show some inhib itory effects of 1,25(OH)

2D and 25(OH)D on B-cell

responses including proliferation, plasma cell dif-ferentiation and secretion of immuno globulins, especially IgG and IgM [23].

1-α-hydroxylaseVDR

Cathelicidin24-hydroxylase

25(OH)D

1,25D

Figure 1. Vitamin D increases immunity. An antigen interacts with a Toll-like receptor. The complex is taken into the cell where the genes for 1-α-hydroxylase and the vitamin D receptor (VDR) are activated. If suffi cient 25(OH)D is present, it is converted to 1,25-dihydroxyvitamin D (1,25[OH]2D) by the 1-α-hydroxylase enzyme. This active form of vitamin D interacts with the VDR and promotes the expression of cathelicidin (a bactericidal peptide) and 24-hydroxylase (the catabolic enzyme that inactivates 1,25[OH]2D, thus completing the reaction). Adapted with permission from Robert P Heaney.


REVIEW Armas

Antigen-presenting cellsDendritic cells and macrophages are key to regulating immune activation and response to self proteins. Both contain an intracellular 1-α-hydroxylase and are capable of producing 1,25(OH)

2D. The latter inhibits the differentia-

tion of monocytes into dendritic cells [24], and also inhibits the antigen-presenting capacity of the cells [25]. Dendritic cells are uniquely capa-ble of signaling to lymphocytes to specialize and migrate to specifi c tissues [26].

The effects of vitamin D on macrophages have some similarities to those on dendritic cells. 1,25(OH)

2D promotes monocyte dif-

ferentiation to macrophages and prevents them from producing infl ammatory cytokines [27]. By inhibit ing antigen-presenting cells from produc-ing cytokines (specifi cally IL-2) that activate Th1 cells or stimulating their production of cytokines (IL-10) that inhibit Th1, 1,25(OH)

2D

modulates the immune system to become more self-tolerant [28–30].

Research to dateMuch has been done in this fi eld in determining the effects of vitamin D on calcium and bone, but this review will focus exclusively on work in the immune system (see TABLE 1).

Infectious disease The connection between infectious diseases and vitamin D is well over 100 years old. It was well known that patients with rickets were more prone to infections and disease mortality was, in large part, due to lung infections such as pneumonia.

TBLong before anti-TB drugs were developed, TB patients were treated by exposure to the sun. Interestingly, in 1946, Dr Raab was using native vitamin D as a bactericidal agent by injecting it directly into the pleural cavity of TB patients who were too ill to undergo lung resection, the standard treatment for pleural TB at that time [31]. He reported that the pleural fl uid was nega-tive for TB bacilli after 3 weeks of vitamin D treatment, and all but one patient clinically improved as well. This work was forgotten when effective TB antibiotics were developed. However, in the basic science fi eld, 1,25(OH)

2D

was known to inhibit the development of TB in macrophage cultures [32].

Recent studies have found associations between high rates of TB infection and vita-min D defi ciency in immigrants in London [33] and in immigrants in Australia [34]. While associ-ation studies suggest, but do not prove, causality,

1,25(OH)2D

Th1cell

Th1cell

Th2cells

–

–

–

+

Antigenpresentingcell

IL-10

XIL-2

IFNγIL-2TNFα

XAntigen

Figure 2. The effect of vitamin D on immune cells. 1,25-dihydroxyvitamin D (1,25[OH]2D) directly inhibits the Th1 lymphocyte from producing infl ammatory cytokines (IFN-γ, IL-2 and TNF-α). 1,25(OH)2D also indirectly inhibits the Th1 lymphocyte by inhibiting the antigen-presenting cell from producing IL-2 and inducing it to produce IL-10, which inhibits Th1 lymphocytes. 1,25(OH)2D promotes Th2 cell development.



a recent randomized clinical trial successfully used 10,000 IU of native vitamin D daily in addition to standard TB multidrug treatment to improve clearance of mycobacterium from spu-tum [35]. The placebo group had 76% sputum conversion, while the vitamin-D-treated group had 100% conversion. Martineau and colleagues also conducted a randomized, controlled trial using a single dose of 100,000 IU native vita-min D to enhance antimycobacterial immunity in tuberculin skin-test-positive patients [36].

Respiratory infectionsEpidemiologic data have shown an association between season and epidemic infl uenza. This has been hypothesized to be related to the sea-sonal differences in vitamin D status [37,38]. Low serum levels of 25(OH)D were also asso-ciated with increased respiratory infections in an Indian study [12], and there was a 13-times greater rate of pneumonia in Ethiopian chil-dren [39]. A Finnish study found an association between low 25(OH)D levels and a variety of acute respiratory infections in army recruits [40]. Further evidence of a possible cause and effect relationship was provided by a 3-year, double-blind, placebo- controlled trial of native vita-min D supplementation in African–American women. Reported cases of infl uenza were lower in the vitamin-D-treated group than the placebo group. This effect was especially pronounced in the winter [41].

Helicobacter pyloriA group of elderly female nursing home residents with osteoporosis who had been treated for over 20 years with α-calcidiol (1α (OH)D

3), a vita-

min D analog, had lower rates of Helicobacter pylori infections than patients who were not treated [42].

When we consider the evidence that vita-min D is needed to initiate a bactericidal response against TB, these fi ndings are highly suggestive of the protective effect of vitamin D against other infections. Further basic research into the effect of vitamin D on different bacteria and viruses is needed. Randomized, controlled clinical tri-als with infectious disease as a predefi ned out-come are also needed to determine the effi cacy of vitamin D and its dose–response relationship to infectious disease prevention.

Autoimmune diseases Epidemiological studies have linked auto-immune diseases such as MS, IBD, RA, sys-temic lupus erythematosus (SLE) and T1D to latitude [43–45]. I will review here further work that has been carried out in mouse models on these diseases, observational studies and a few randomized, controlled trials. All of these autoimmune diseases are mediated by specifi c T lymphocytes, Th1 cells. These cells are inhib-ited both directly and indirectly by 1,25(OH)

2D

in cell cultures.The cause of autoimmune diseases is mul-

tifactorial. With the high prevalence of vita-min D defi ciency in the general population, it is unlikely that this is the only factor predis-posing someone to autoimmune disease. There appears to be a genetic component involved as well as environmental factors, such as viruses, that predispose a person to develop an autoim-mune disease. Vitamin D defi ciency appears to be one modifi able factor in autoimmunity development.

Infl ammatory bowel diseaseIBD is an immune (Th1)-mediated disease with infl ammation focused on the GI tract. The prev-alence of IBD exhibits a north–south latitude

Table 1. Evidence of vitamin D effects on disease.

Disease Mice models Epidemiology Observational RCTs

TB √ √

Respiratory infections √ √ √

Infl ammatory bowel √ √ √

Multiple sclerosis √ √ √ √

Rheumatoid arthritis √ -- ±

Lupus erythematosus √ ±

Type 1 diabetes √ √ √ ±

√: Evidence present; ±: Evidence mixed; --: Evidence negative.RCT: Randomized controlled trial.


REVIEW Armas

gradient similar to that of MS [46]. Seasonal exacerbation of IBD has been described with higher incidence in the winter [47].

Vitamin D defi ciency is quite common in patients with IBD, possibly caused by a poor dietary intake, poor absorption, lack of sun exposure and/or steroid use, which affects vita-min D metabolism. Several studies have looked at the prevalence of vitamin D defi ciency in patients with IBD. The defi nition of vitamin D defi ciency varies throughout the various studies; some use 25(OH)D levels of less than 15 ng/dl as being indicative of vitamin D defi ciency, while others use a higher level, 20–32 ng/ml. One study showed 30% of the subjects with IBD having 25(OH)D levels below 16 ng/ml [48]. In the Manitoba IBD Cohort study, the investigators found that 80% of recently diagnosed IBD patients had 25(OH)D levels of less than 30 ng/ml [49]. Another study in children and young adults aged 5–22 years, found 25(OH)D levels of less than 15 ng/ml in 16% of the patients, and looking at their data further, it appears that approximately 80% of the patients had vitamin D levels below 30 ng/ml [50]. Another study of vitamin D status in children found a high prevalence of vitamin D defi ciency of approximately 38% using a level of 15 ng/ml, and approximately 80% using a level of 32 mg/ml. This study also found an associa-tion between low vitamin D status and winter, having dark skin, a low body mass index, high sedimentation rate, new diagnosis or upper GI tract disease involvement. They found the most predictive factor in low vitamin D status to be low albumin levels [51]. Vitamin D bound to vitamin-D-binding protein could potentially be lost through the gut lumen as the loss of albumin and immunoglobulins is well documented in IBD [52]. The association of vitamin D defi ciency with IBD is quite strong, but it does not point to a cause and effect relationship. While it is quite likely that the IBD would cause vitamin D defi -ciency, whether the vitamin D defi ciency plays a role in the onset of IBD remains to be seen. The experimental studies in mice point to the likely role that vitamin D plays in IBD.

In mouse models of IBD, it has been demon-strated that absent vitamin D receptors or IL-10 defi ciency add to the symptoms of colitis [53]. Vitamin D defi ciency accelerates the develop-ment of IBD in experimental models [54]. Also in a mouse model, 1,25(OH)

2D prevents and

amelio rates the symptoms of IBD [55]. Vitamin D analogs have been used in lieu of 1,25(OH)

2D to

avoid the risk of hypercalcemia. The vitamin D analog, 22-ene-25-oxa vitamin D, was used in an IBD mouse model to reduce colitis severity. It did this without causing hypercalcemia and it was noted that the infl ammatory cytokines TNF-α and IFN-γ were reduced as well [56]. The vitamin D analog 1α (OH)D

3 has also been used

to prevent colitis in mice [57].Vitamin D uses at least two mechanisms to

reduce infl ammation in IBD; reducing infl am-matory cytokines and maintaining the intes-tinal mucosal barrier. As in other autoimmune diseases, reduction of infl ammatory cytokines is an important part of reducing infl ammation. Treatment of mice with 1,25(OH)

2D decreases

TNF-α production, but this effect was greatest if high dietary calcium was also used in the treat-ment [58]. Treating cells from Crohn’s disease and ulcerative colitis patients with a vitamin D analog decreased the production of TNF-α [59]. Treating T cells from Crohn’s patients with a combination of 1,25(OH)

2D and dexametha-

sone downregulated IFN-γ and increased pro-duction of IL-10. Interestingly, the cytokines had the same response when 1,25(OH)

2D was

used by itself in the absence of dexametha-sone [60]. There also appears to be a direct effect of 1,25(OH)

2D on the intestinal barrier. It has

been recently demonstrated in mouse models that 1,25(OH)

2D and the vitamin D receptor

are needed to maintain the intestinal mucosa barrier. It does this through enhancing intra-cellular junctions and healing mucosal injuries. 1,25(OH)

2D also increases tight junctions in cell

cultures [61].While the murine models and basic science

is strong for suggesting the role of vitamin D in IBD, the levels of 25(OH)D needed for pre-vention or treatment have not been determined. There also needs to be more clinical intervention trials in humans.

Rheumatoid arthritisRA is an immune (Th1)-mediated disease caus-ing infl ammation and subsequent destruction of joints. The data supporting vitamin D preven-tion or treatment of RA is not as strong as for the other diseases, but it does show the same T-mediated autoimmunity and so, theoretically, should be infl uenced by vitamin D status. Unlike some of the other autoimmune diseases, RA has not been shown to be related to latitude [62]. Mouse models have been developed that imitate RA. These include Lyme-induced arthritis and collagen-induced arthritis, and 1,25(OH)

2D has



been shown to prevent initiation and progres-sion of infl ammatory arthritis in these mouse models [63].

In human studies the association between vita-min D status and RA has been mixed. Vitamin D defi ciency has been noted in patients with RA [64]. A recent large observational study reported higher disease activity in spring and lower in autumn, which may be a result of waning vitamin D stores during winter. Unfortunately, 25(OH)D levels were not assessed as part of this study [65]. In Europe, serum measurements of 25(OH)D have been inversely related to the severity of RA [66]. Another study did not fi nd a relationship between 25(OH)D levels and disease activity, measured as C-reactive protein or erythrocyte sedimentation rate [67,68]. This was carried out in patients on active treatment, which could mask the potential role of vitamin D. A study performed with newly diagnosed patients before treatment did fi nd an inverse correlation between 25(OH)D levels and disease activity [20].

The Women’s Iowa Health Study, a large observational study, found that vitamin D intake from food and supplements was inversely cor-related with RA incidence [69]. Interestingly enough, this study also found an inverse relation-ship between milk products and RA. However, since many milk products are fortifi ed with vita-min D, this study could not separate out the effects. As an aside, many of the mouse models that studied human autoimmune disease also noted that the effect of vitamin D on disease was blunted, unless the animal was on a high calcium diet, indicating that it is likely other nutritional factors play a role. Another large prospective observational study, The Nurses Health Study I and II, did not fi nd a relationship between native vitamin D intake and RA. They also did not have serum 25(OH)D measure-ments, but they did take into account variables such as skin color, latitude and UV exposure to make an estimate of vitamin D production in the skin [70]. A retrospective study in the Netherlands obtained 25(OH)D levels from blood donors who later developed RA. In this study they did not see an association between vitamin D defi ciency, defi ned as less than 8 ng/ml, and the development of RA [71]. However, this study used such a low cut-off to indicate vitamin D defi ciency that they may not have seen an effect if a higher level was needed for pre-vention. Only one clinical treatment trial used a vitamin D analog, 1α (OH)D

3, in an open-label

trial of RA patients with some success [72,73]. A

controlled, randomized trial of native vitamin D for RA prevention or treatment has not been published. Much more work needs to be done in determining the optimal level of 25(OH)D needed to prevent or treat RA.

Multiple sclerosisMS is an immune (Th1) mediated, infl amma-tory, demyelinating disease of the CNS. Much of the literature linking vitamin D and MS has been epidemiological and observational in nature. Basic science work has been done in mice with experimental allergic encephalitis (EAE; a useful animal model of MS). In this model, vitamin D defi ciency exacerbates EAE and treat-ment with vitamin D suppresses expression of EAE [74].

It has been observed that MS prevalence is related to latitude, with higher incidence occur-ring at a greater distance from the equator. It has also been noted that there is a seasonal fl uc-tuation in appearance of new brain lesions on MRI, with more active lesions being seen in the spring compared with the fall [44]. The sea-sonal fl uctuation in MS exacerbations has also been associated with lower 25(OH)D levels [75]. In large observational studies (Nurses Health Study I and II), women with the highest levels of vitamin D intake, largely from multivitamin supplements, were 40% less likely to develop MS [76]. Measurements of 25(OH)D in a subset of these subjects with the highest intake had a mean 25(OH)D level of approximately 30 ng/ml. One case–control analysis in the Netherlands found that, in women, for every 4 mg/dl increase in serum 25(OH)D levels, the odds ratio for develop ing MS decreased by 19% [77]. This study also found an inverse relationship between disa-bility score and 25(OH)D levels. A retrospective study of USA military personnel using stored serum samples found increased MS risk in those with lower 25(OH)D levels. They calculated an odds ratio of 0.59 for a 20 ng/ml increase in 25(OH)D levels [78].

MS patients are at high risk of vitamin D defi ciency. One study found that at the time of diagnosis, more than 64% of MS patients had 25(OH)D levels below 20 mg/dl [79]. All of these observations have led to the suggestion that native vitamin D or 1,25(OH)

2D supplement-

ation may reduce the development of MS [80]. Unfortunately, clinical trial evidence is limited. A year long open-label trial of 1,25(OH)

2D was

done in relapsing–remitting patients with MS. This study did not have a control group so it


REVIEW Armas

is diffi cult to assess effi cacy, although they had fewer relapses during the treatment part of the trial compared with the following year. Two of the subjects did have symptomatic hyper calcemia and two subjects required dose adjustments for asymptomatic hypercalcemia [81]. Vitamin D analogs have been tried experimentally because of the risk of hypercalcemia with active vita-min D (1,25(OH)

2D). 1α (OH)D

3, a vitamin D

analog, was administered to fi ve MS patients for 6 months [82]. Another vitamin D analog, 19-nor-1,25-dihydroxyvitamin D

2, was used

in 11 patients with relapsing–remitting MS for 6 months. In this study, there were no changes in clinical symptoms or MRI lesions [83].

Now that we know that cells make 1,25(OH)2D

internally, it makes sense to try native vita-min D supplements. A 6-month, double-blind, randomized, controlled trial of 1000 IU native vitamin D daily versus a placebo in MS patients found a signifi cantly increased level of the anti-infl ammatory cytokine, TGF-β-1, in the native vitamin-D-treated group [84]. TGF-β-1 is a cytokine that has been found to be inversely cor-related with symptoms and level of disability in patients with MS [85]. Another small treatment trial using magnesium, calcium and cod liver oil containing 5000 IU native vitamin D was con-ducted in subjects with MS. In this study, the numbers of MS exacerbations were reduced (nine) compared with the patients’ expected exacerba-tion rate (25) [86]. A tolerability trial of vitamin D in MS patients using escalating doses of up to 280,000 IU weekly over 28 weeks in MS patients did not increase serum or urine calcium concen-trations. These huge doses did not effect clinical disease progression or activity, but did decrease the number of lesions seen on MRI [87].

Overall, the association studies and the basic science data are quite strong in suggesting an effect of vitamin D on MS. The effect on MS exacer-bations is likely to be through reducing infl am-mation, but 25(OH)D may also have a direct effect on muscle. Other studies have shown that native vitamin D supplementation increases mus-cle strength [88]. The effi cacy of treating or pre-venting MS with vitamin D is largely unknown. Studies to determine optimal 25(OH)D levels to prevent MS or to decrease MS exacerbations are needed. There is a great need for controlled clinical trials addressing these outcomes.

Type 1 diabetes mellitusT1D is an autoimmune disorder characterized by destruction of the pancreatic islet cells. As

with other autoimmune diseases, T1D has been shown to have a latitude gradient, with higher rates found in areas with lower UV-B irradiance. It has been noted that T1D is almost nonexist-ent in areas with high UV-B irradiance [89,90]. There is also a seasonal variation in incidence of T1D diagnosis [91]. A study in Newfoundland, Canada, reported peak T1D incidence in the winter months when UV-B exposure and the production of vitamin D is negligible [92].

It is known that both newly diagnosed dia-betic patients and those with established disease have lower 25(OH)D and 1,25(OH)

2D levels

than age- and sex-matched controls [93–95]. In Sweden, investigators found low 25(OH)D lev-els in patients who were newly diagnosed with T1D. In this population, they saw greater rates of both T1D and vitamin D defi ciency in young men compared with women. They postulated that the increased incidence of the T1D could be partially related to vitamin D defi ciency [87].

In several Nordic countries, vitamin D supple-mentation of infants was recommended. There have been several case–control studies that have examined the effects of cod liver oil or native vitamin D supplementation during pregnancy or infancy on later development of T1D. The results of these studies have not always been congruent depending on the design of the study, which variables were included and the timing of supplementation. Hyppönen conducted a birth cohort study in Finland where high levels of vitamin D supplementation (2000 IU daily) were recommended in infants. She found that children who were compliant with this recom-mendation had a decrease in frequency of T1D (relative risk was 0.12, 95% confi dence interval was 0.03–0.51) compared with those without supplementation [96]. The source of native vita-min D was from cod liver oil as well as other native vitamin D supplements. In Sweden, native vitamin D supplementation of 400 IU is recommended in children, and a study was car-ried out by looking at compliance with native vitamin D supplementation and the incidence of T1D. The investigators noted nearly 100% compliance, so they were unable to compare the effect of vitamin D supplementation. They did fi nd that taking supplements containing vitamin D during pregnancy was associated with lower rates of developing autoantibodies (a risk factor for T1D) in the infants at 1 year [97]. The Diabetes Autoimmunity Study in the Young (DAISY) reported that the presence of autoantibodies in children inversely correlated



with maternal native vitamin D intake from food, but not supplements, during pregnancy [98]. Another case–control study looking at cod liver oil supplementation during pregnancy or early childhood found a decreased rate of T1D in children who used cod liver oil during their fi rst year of life, but did not see an effect of sup-plementing native vitamin D during pregnancy [99]. This study did not ask about the amounts of vitamin D taken, but typical prenatal- and multi-vitamins available contained only 200 IU. Another retro spective case–control study in Italy also found an inverse relationship between native vitamin D supplementation in infancy and the development of T1D [100]. A recent meta-anal-ysis of several of these case–control and cohort studies found that overall the risk of T1D was signifi cantly reduced in infants who were supple-mented with native vitamin D (an odds ratio of 0.71) compared with controls. Most of the cases were supplemented with approximately 400 IU of native vitamin D from either cod liver oil or supplements. They also noted that patients with rickets diagnosed early in life had the greatest risk of developing T1D (with an odds ratio of 3.0) [101]. Unfortunately, these studies did not use 25(OH)D levels to give an objective measure-ment of the levels needed to provide protection from T1D.

In mice models of T1D (nonobese dia-betic mice or NOD model), treatment with 1,25(OH)

2D from the time of weaning reduces

the incidence of insulitis and development of T1D [102,103]. As in other autoimmune diseases, vitamin D analogs have been used to directly stimulate the vitamin D receptor, and these have also been protective [104]. While the mice models have given us some idea of the role vita-min D plays in the incidence of T1D, the Bio-Breeding rat models of diabetes did not have the same response to 25(OH)D, 1,25(OH)

2D

or vitamin D analogs, implying a species-specifi c effect [105].

There have been very few randomized trials looking at the effects of vitamin D metabolites or vitamin D analogs on the incidence or control of diabetes in humans. A randomized, open-label trial investigating 0.25 µg of 1,25(OH)

2D taken

every other day versus niacin in newly diagnosed T1D patients had no major effect on the diabetes, but did decrease insulin requirements slightly. This is likely because the timing and dose of supplementation is so important. It appears that supplementation during pregnancy or infancy has a greater effect than supplementing at the

time of diagnosis, after most of the insulin-producing β-cells have been destroyed. On the other hand, it is encouraging that the patients exhibited some decrease in insulin requirements, and this has been interpreted as protection of residual β-cell function. Unfortunately, in this study there were no measurements of 25(OH)D or 1,25(OH)

2D to indicate the level needed to

improve diabetic control [106]. Another pilot study of late-onset autoimmune diabetes used 1,25(OH)

2D to improve residual β-cell function

as measured by C-peptide secretion [107]. There are many unanswered questions. Before vita-min D supplementation can be used to prevent T1D, the timing and 25(OH)D levels needed must be worked out. As in the other auto immune diseases, there is a need for prospective clinical research in this area.

Systemic lupus erythematosusSystemic lupus erythematosus is a chronic infl ammatory disease of unknown cause which can affect the skin, joints, kidneys, lungs, nervous system, serous membranes and/or other organs of the body. Lupus mouse models treated with vitamin D analogs had improved long evity and decreased proteinuria, renal arteritis and absent alopecia and scab formation [108,109]. Other studies showed no effects on SLE manifestations [110].

Vitamin D defi ciency has been appreciated in patients with SLE [111–115]. The reasons for this could be steroid use, photosensitivity lead-ing to decreased sun exposure, or poor dietary intake related to disease activity. Another rea-son could be antivitamin D antibodies that have been reported in SLE patients [108]. A cross-sec-tional study of 112 SLE patients noted very low 25(OH)D levels (mean: 11.5 ng/ml). This level was seen in both the newly diagnosed patients as well as those with established disease, and it was not related to renal disease or to steroid use [109]. A cross-sectional study found that 65% of patients with SLE had vitamin D defi ciency and 25(OH)D levels inversely correlated with disease severity [116]. Other studies have also shown the relationship between serum levels of 25(OH)D and scores of severity [117,118]. African–Americans, who tend to have a higher prevalence of vita-min D defi ciency due to the melanin content of their skin, have a higher incidence and severity of SLE [119].

On the other hand, a large prospective obser-vational study, the Nurses Health Study I and II, found no correlation with SLE incidence and vitamin D intake from food or supplements [70].


REVIEW Armas

The lack of fi nding in this large study may be explained by the fact that vitamin D intake from food or supplements contributes a very small amount to vitamin D status compared with sun exposure. Another cross-sectional study found vitamin D defi ciency in 75% of patients with no relation to disease severity [120]. Interestingly, they did fi nd that subjects with very low 25(OH)D levels, those with less than 10 ng/ml, had a high score on their fatigue scale. It has been noted in clinical patients that treating SLE patients with 800 IU native vitamin D

3 reduced reported

fatigue episodes [121]. The association of vita-min D with SLE is clear, but the evidence for the treatment or prevention of SLE with vitamin D is unknown at this point. Further clinical research needs to be done.

OtherPeriodontal disease is a chronic infl ammatory disease characterized by loss of periodontal attachment. It has elements of both autoimmune and infectious disease. The host’s production of proinfl ammatory cytokines to bacteria in dental plaque leads to the damage. The Third National Health and Examination Study (NHANES III) found that 25(OH)D concentrations were inversely correlated with periodontal attachment loss in older adults [122].

Clinical implicationsThe defi nition of vitamin D suffi ciency has been established with calcium system end points, including parathyroid hormone response [2], calcium absorption [4] and bone mineral density measurements [123]. These end points are optimal when 25(OH)D is at approximately 30–34 ng/ml. Unfortunately, we do not have the data to establish the level of 25(OH)D that is suffi cient for optimal function of the immune system. It may well be that more vitamin D is required to protect against infections, autoimmune diseases or cancer. This was suggested in work by Lappe and colleagues, which described a decrease in can-cer incidence in a randomized, controlled trial of vitamin D and calcium when 25(OH)D levels increased from 28.8 ± 8.0 ng/ml to 38.5 ± 8.6 ng/ml [124]. Recommendations to keep 25(OH)D lev-els above 30 ng/ml are based on current consensus from data collected on calcium homeostasis end points [2,4,123]. Others have suggested that even higher levels (e.g., 36–40 ng/ml) may be needed to affect outcomes such as bone mineral density, lower-extremity function, dental health, and risk of falls, fractures and colorectal cancer [123,125].

Native vitamin D can be obtained through sun exposure or oral supplements, and in some coun-tries intramuscular injections of native vitamin D are also available. Oral supplements of native vita-min D are the simplest way for a person to get an adequate amount. Nutritional supplements of vitamin D come in two forms: vitamin D

2

(ergocalciferol) and vitamin D3 (cholecalciferol).

Several studies have shown that intermittent doses of vitamin D

3 are between three- and nine-times

more potent at maintaining 25(OH)D levels than D

2 [126–128]. This has been recently challenged by

Holick’s work in which he showed that daily vita-min D

2 or vitamin D

3 doses were equally effec-

tive at maintaining 25(OH)D levels [129]. This is consistent with previous studies that show initial 25(OH)D levels to be equal after dosing with native vitamin D

2 or D

3, suggesting that absorp-

tion and 25-hydroxylation are the same [4].The differences between the two forms of vitamin D may become apparent only during further steps in metabolism or in action on the VDR. The differences between the fi ndings of these studies are possibly due to the daily versus intermittent dosing regimen. Further studies need to clarify whether or not there is a true difference between the forms of vitamin D. We currently use vita-min D

3 because the majority of the clinical trials

with bone mineral density and fracture outcomes were conducted using a native vitamin D

3 supple-

ment rather than D

2. The associations between

higher 25(OH)D levels and lower incidence of infectious disease, autoimmune disease and can-cer were observed in people whose vitamin D was mainly derived from sun exposure. There needs to be further basic science research exploring the action of vitamin D on the VDR to confi rm if the forms are truly interchangeable.

The question always arises as to how much to give. Rather than rely on a ‘one-size-fi ts-all’ recommendation, which does not account for differences in skin pigmentation, sun exposure, age or weight, the simplest method is to measure the patient’s 25(OH)D level. In calculating sup-plement dose, an estimate is that 100−150 IU daily will raise 25(OH)D levels by approxi-mately 1 ng/ml [130]. In practice, this translates to between 1000 and 2000 IU daily for typical patients with baseline 25(OH)D levels greater than 10 ng/ml. Occasionally, patients with malabsorption or gastrointestinal surgery may require substantially more vitamin D.

Vitamin D has experienced an explosion of popularity recently and hence, supplements are much easier to fi nd in the USA. Vitamin D

2 is



available in some multivitamin preparations and is also available as a prescription preparation of 50,000 IU. In addition, vitamin D

3 is available

in multivitamin supplements as well as over-the-counter preparations of 200–50,000 IU. Availability is signifi cantly different in other countries. In the UK, vitamin D

2 is the form

most readily available, either combined with calcium or in over-the-counter preparations. Vitamin D

3 is typically prepared in calcium

supplements as 400 IU increments, and is also available as over-the-counter supplements [131]. With vitamin D available to the general popula-tion, caution must be given, as toxicity can be a risk. From studies of case reports of toxicity and controlled dosing studies, it appears that the daily tolerable upper limit is approximately 10,000 IU [132]. This is a much greater amount than is needed by a typical patient. As we defi ne what is an optimal 25(OH)D level for different disease states, we will need more dosing studies to clarify safety.

ConclusionThe evidence for the role of vitamin D in pre-vention and treatment of autoimmune diseases is just beginning to accumulate. The studies from basic science, mice models and epide-miologic studies point to a protective role of vitamin D in the immune system. Vitamin D defi ciency is highly prevalent in the general healthy population, and even more prevalent in those with chronic disease. It is undisputed that vitamin D suffi ciency is essential for opti-mal bone health. As moderate amounts of sup-plemental vitamin D are safe, it makes sense to treat and avoid vitamin D defi ciency while the evidence for the role of vitamin D in the immune system accumulates.

Future perspectiveIn the future, we will have a thorough under-standing of the multiple mechanisms that vitamin D uses to affect cells throughout the body. There will be many more randomized,

Executive summary

The prevalence of vitamin D defi ciency is high among the general population. The history of vitamin D discovery

The vitamin D receptor is found in many different tissues and cells throughout the body. The 1- α-hydroxylase is also present in many different tissues and cells and can convert 25-hydroxyvitamin D (25[OH]D) to the active vitamin D metabolite, 1,25 dihydroxyvitamin D (1,25[OH]2D).

Vitamin D physiologyVitamin D is formed in the skin, hydroxylated by the liver and then the kidney. 25(OH)D can also be hydroxylated by intracellular 1- α-hydroxylase for each individual cell’s internal use.Through the vitamin D receptor, 1,25(OH) 2D acts on vitamin D response elements on the genome to regulate gene transcription.These genes are responsible for calcium homeostasis, bone remodeling and cell regulation, including proliferation, differentiation and apoptosis.

Mechanism of vitamin D in the immune systemThere are two distinct end points of the effect of vitamin D on the immune system:

Increased immunity against antigens- Modulation of the immune response against the body (self)-

Current clinical researchVitamin D has protective effects against infectious diseases such as TB. Vitamin D defi ciency is associated with immune-mediated diseases:

Multiple sclerosis- Infl ammatory bowel disease- Rheumatoid arthritis- Systemic lupus erythematosus - Type 1 diabetes-

Clinical implications25(OH)D is the form of vitamin D clinically measured to assess vitamin D status. Calcium system end points support a 25(OH)D level of approximately 30 ng/ml. Oral native vitamin D supplementation is the simplest way to get vitamin D. 100 −150 IU of native vitamin D daily will raise 25(OH)D levels by approximately 1 ng/ml.

ConclusionVitamin D defi ciency should be prevented and treated, while the evidence for its role in the immune system accumulates.


REVIEW Armas

controlled studies that will address the effi cacy of native vitamin D. We will know the optimal levels of 25(OH)D needed to impact specifi c endpoints such as infectious disease, auto-immune disease and cancer. There will be fur-ther recommendations on vitamin D intake for the population as a whole to reap the benefi ts of optimal vitamin D status.

Financial & competing interests disclosureThe author has no relevant affi liations or fi nancial involve-ment with any organization or entity with a fi nancial interest in or fi nancial confl ict with the subject matter or materials discussed in the manuscript. This includes employment, con-sultancies, honoraria, stock ownership or options, expert tes-timony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

BibliographyPapers of special note have been highlighted as: of interest of considerable interest

Thomas KK, Lloyd-Jones DM, Thadhani RI 1

et al.: Hypovitaminosis D in medical inpatients. N. Engl. J. Med. 338, 777–783 (1998).

Chapuy MC, Preziosi P, Maamer M 2 et al.: Prevalence of vitamin D insuffi ciency in an adult normal population. Osteoporos Int. 7, 439–443 (1997).

Holick MF, Siris ES, Binkley N 3 et al.: Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy. J. Clin. Endocrinol. Metab. 90, 3215–3224 (2005).

Heaney RP, Dowell MS, Hale CA, Bendich 4

A: Calcium absorptirron varies within the reference range for serum 25-hydroxyvitamin D. J. Am. Coll. Nutr. 22, 142–146 (2003).

Gordon CM, DePeter KC, Feldman HA, 5

Grace E, Emans SJ: Prevalence of vitamin D defi ciency among healthy adolescents. Arch. Pediatr. Adolesc. Med. 158, 531–537 (2004).

Sullivan SS, Rosen CJ, Halteman WA, Chen 6

TC, Holick MF: Adolescent girls in Maine at risk for vitamin D insuffi ciency. J. Am. Diet. Assoc. 105, 971–974 (2005).

Tangpricha V, Pearce EN, Chen TC, Holick 7

MF: Vitamin D insuffi ciency among free-living healthy young adults. Am. J. Med. 112, 659–662 (2002).

Vitamin D defi ciency is common in healthy

young people.

Marwaha RK, Tandon N, Reddy D 8 et al.: Vitamin D and bone mineral density status of healthy schoolchildren in northern India. Am. J. Clin. Nutr. 82, 477–482 (2005).

Levis S, Gomez A, Jimenez C 9 et al.: Vitamin D defi ciency and seasonal variation in an adult south Florida population. J. Clin. Endocrinol. Metab. 90(3), 1557–1562 (2005).

Holick MF: Sunlight and vitamin D for bone 10

health and prevention of autoimmune diseases, cancers and cardiovascular disease. Am. J. Clin. Nutr. 80(6 Suppl.), 1678S–1688S (2004).

Holick MF: Vitamin D for health and in 11

chronic kidney disease. Semin. Dial. 18, 266–275 (2005).

Wayse V, Yousafzai A, Mogale K, Filteau S: 12

Association of subclinical vitamin D defi ciency with severe acute lower respiratory infection in Indian children under 5 y. Eur. J. Clin. Nutr. 58, 563–567 (2004).

Bringhurst F, Demay M, Kronenberg H: 13

Hormones and disorders of mineral metabolism. In: Williams Textbook of Endocrinology (11th Edition). Kronenberg HM, Melmed S, Polonsky KS, Larsen PR (Eds). WB Saunders Company, PA, USA, 1155–1209 (2008).

Liu PT, Stenger S, Li H 14 et al.: Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311, 1770–1773 (2006).

Herr C, Shaykhiev R, Bals R: The role of 15

cathelicidin and defensins in pulmonary infl ammatory diseases. Expert Opin. Biol. Ther. 7, 1449–1461 (2007).

Howell MD, Wollenberg A, Gallo RL 16 et al.: Cathelicidin defi ciency predisposes to eczema herpeticum. J. Allergy Clin. Immunol. 117, 836–841 (2006).

Laube DM, Yim S, Ryan LK, Kisich KO, 17

Diamond G: Antimicrobial peptides in the airway. Curr. Top. Microbiol. Immunol. 306, 153–182 (2006).

Mahon BD, Wittke S, Weaver V, 18

Cantorna MT: The targets of vitamin D depend on the differentiation and activation status of CD4-positive T cells. J. Cell. Biochem. 89, 922–932 (2003).

Cantorna MT, Zhu Y, Froicu M, Wittke A: 19

Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system. Am. J. Clin. Nutr. 80, 1717S–1720S (2004).

Patel S, Farragher T, Berry J, Bunn D, Silman 20

A, Symmons D: Association between serum vitamin D metabolite levels and disease activity in patients with early infl ammatory polyarthritis . Arthritis Rheum. 56, 2143–2149 (2007).

Nashold FE: Rag-1-dependent cells are 21

necessary for 1,25-dihydroxyvitamin D(3) prevention of experimental autoimmune

encephalomyelitis. J. Neuroimmunol. 119, 16–29 (2001).

Mathieu C, Badenhoop K: Vitamin D and 22

Type 1 diabetes mellitus: state of the art. Trends Endocrinol. Metab. 16, 261–266 (2005).

Chen S, Sims GP, Chen XX, Gu YY, Chen S, 23

Lipsky PE: Modulatory effects of 1,25-hydroxyvitamin D3 on human B cell differentiation. J. Immunol. 179, 1634–1647 (2007).

Griffi n MD, Lutz W, Phan VA, Bachman LA, 24

McKean DJ, Kumar R: Dendrtic cell modulation by 1α,25 dihydroxyvitamin D3 and its analogs: a vitamin D receptor-dependent pathway that promotes a persistent state of immaturity in vitro and in vivo. Proc. Natl Acad. Sci. USA 98, 6800–6805 (2001).

Griffi n MD, Lutz WH, Phan VA, Bachman 25

LA, McKean DJ, Kumar R: Potent inhibition of dendritic cell differentiation and maturation by vitamin D analogs. Biochem. Biophys. Res. Commun. 270, 701–708 (2000).

Sigmundsdottir H, Butcher EC: 26

Environmental cues, dendritic cells and the programming of tissue-selective lymphocyte traffi cking. Nat. Immunol. 9, 981–987 (2008).

Helming L, Bose J, Ehrchen J27 et al.: 1α,25-dihydroxyvitamin D3 is a potent suppressor of interferon γ-mediated macrophage activation. Blood 106, 4351–4358 (2005).

Mattner F: Inhibition of Th1 development 28

and treatment of chronic-relapsing experimental allergic encephalomyelitis by a non-hypercalcemic analogue of 1,25-dihydroxyvitamin D(3). Eur. J. Immunol. 30, 498–508 (2000).

D’Ambrosio D, Cippitelli M, Cocciolo MG 29

et al.: Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3: involvement of NF-κB downregulation in transcriptional repression of the p40 gene. J. Clin. Invest. 101, 252–262 (1998).

Arnson Y, Amital H, Shoenfeld Y: Vitamin D 30

and autoimmunity: new aetiological and therapeutic considerations. Ann. Rheum. Dis. 66, 1137–1142 (2007).



Raab W: Vitamin D – its bactericidal action. 31

Chest 12, 409–415 (1946).

Rook GA, Steele J, Fraher L 32 et al.: Vitamin D3, interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes. Immunology 57, 159–163 (1986).

Wilkinson RJ, Llewelyn M, Toossi Z 33 et al.: Infl uence of vitamin D defi ciency and vitamin D receptor polymorphisms on tuberculosis amongst Gujarati Asians in West London: a case–control study. Lancet 355, 618–621 (2000).

Gibney KB, MacGregor L, Leder K 34 et al.: Vitamin D defi ciency is associated with tuberculosis and latent tuberculosis infection in immigrants from sub-Saharan Africa. Clin. Infect. Dis. 46(3), 443–446 (2008).

Nursyam EW, Amin Z, Rumende CM: The 35

effect of vitamin D as supplementary treatment in patients with moderately advanced pulmonary tuberculous lesion. Acta Med. Indones. 38, 3–5 (2006).

Demonstrates the effect of supplementary

native vitamin D on TB treatment.

Maerineau AR, Wilinson RJ, Wilkinson KA36 et al.: A single dose of vitamin D enhances immunity to mycobacteria. Am. J. Respir. Crit. Care Med. 176, 208–213 (2007).

Cannell JJ, Vieth R, Umhau C37 et al.: Epidemic infl uenza and vitamin D. Epidemiol. Infect. 134, 1129–1140 (2006).

Cannell JJ, Zasloff M, Garland F, Scragg R, 38

Giovannucci E: On the epidemiology of infl uenza. Virol. J. 5, 29 (2008).

Muhe L, Lulseged S, Mason KE, 39

Simoes EAF: Case–control study of the role of nutritional rickets in the risk of developing pneumonia in Ethiopian children. Lancet 349, 1801–1804 (1997).

Laaksi I, Ruohola JP, Tuohimaa P40 et al.: An association of serum vitamin D concentrations <40 nmol/l with acute respiratory tract infection in young Finnish men. Am. J. Clin. Nutr. 86, 714–717 (2007).

Aloia JF, Li-Ng M: Re: epidemic infl uenza 41

and vitamin D. Epidemiol. Infect. 134, 1129–1130 (2007).

Kawarau A, Takeda N, Tanida K 42 et al.: Inhibitory effect of long term 1-α-hydroxyvitamin D3 administration on Helicobacter pylori infection. J. Clin. Biochem. Nutr. 38, 103–106 (2006).

Grant WB: Epidemiology of disease risks in 43

relation to vitamin D insuffi ciency. Prog. Biophys. Mol. Biol. 92, 65–79 (2006).

Embry AF, Snowdon LR, Vieth R: Vitamin D 44

and seasonal fl uctuations of gadolinium-enhancing lesions in multiple sclerosis. Ann. Neurol. 48, 271–272 (2000).

Lin R, White JH: The pleiotropic actions of 45

vitamin D. Bioessays 26, 21–28 (2004).

Loftus EV Jr: Clinical epidemiology of 46

infl ammatory bowel disease: incidence, prevalence, and environmental infl uences. Gastroenterology 126, 1504–1517 (2004).

Moum B, Aadland E, Ekbom A, Vatn MH: 47

Seasonal variations in the onset of ulcerative colitis. Gut 38, 376–378 (1996).

Siffl edeen JS, Siminoski K, Steinhart H, 48

Greenberg G, Fedorak RN: The frequency of vitamin D defi ciency in adults with Crohn’s disease. Can. J. Gastroenterol. 17, 473–478 (2003).

Leslie WD, Miller N, Rogala L, 49

Bernstein CN: Vitamin D status and bone density in recently diagnosed infl ammatory bowel disease: the Manitoba IBD Cohort Study. Am. J. Gastroenterol 103, 1451–1459 (2008).

Sentongo TA, Semaeo EJ, Stettler N, Piccoli 50

DA, Stallings VA, Zemel BS: Vitamin D status in children, adolescents, and young adults with Crohn disease. Am. J. Clin. Nutr. 76, 1077–1081 (2002).

Pappa HM, Gordon CM, Saslowsky TM 51

et al.: Vitamin D status in children and young adults with infl ammatory bowel disease. Pediatrics 118, 1950–1961 (2006).

Pappa HM, Grand RJ, Gordon CM: Report 52

on the vitamin D status of adult and pediatric patients with infl ammatory bowel disease and its signifi cance for bone health and disease. Infl amm. Bowel Dis. 12, 1162–1174 (2006).

Froicu M, Weaver V, Wynn TA, 53

McDowell MA, Welsh JE, Cantorna MT: A crucial role for the vitamin D receptor in experimental infl ammatory bowel diseases. Mol. Endocrinol. 17, 2386–2392 (2003).

Bises G, Kallay E, Weiland T54 et al.: 25-hydroxyvitamin D3–1α-hydroxylase expression in normal and malignant human colon. J. Histochem. Cytochem. 52, 985–989 (2004).

Cantorna MT, Munsick C, Bemiss C, Mahon 55

BD: 1,25-dihydroxycholecalciferol prevents and ameliorates symptoms of experimental murine infl ammatory bowel disease. J. Nutr. 130, 2648–2652 (2000).

Daniel C, Radeke HH, Sartory NA 56 et al.: The new low calcemic vitamin D analog 22-eme-25-oxa-vitamin D prominently ameliorates T helper cell Type 1-mediated colitis in mice. J. Pharmacol. Exp. Ther. 319, 622–631 (2006).

Kikuchi H, Murakami S, Suzuki S, Kudo H, 57

Sassa S, Sakamoto S: Chemopreventive effect of a vitamin D3 analog, alfacalcidol, on colorectal carcinogenesis in mice with ulcerative colitis. Anticancer Drugs 18, 1183–1187 (2007).

Zhu Y, Mahon BD, Froicu M, Cantorna MT: 58

Calcium and 1α,25-dihydroxyvitamin D3 target the TNF-α pathway to suppress experimental infl ammatory bowel disease. Eur. J. Immunol. 35, 217–224 (2005).

Stio M, Martinesi M, Bruni S 59 et al.: Interaction among vitamin D(3) analogue KH 1060, TNF-α, and vitamin D receptor protein in peripheral blood mononuclear cells of infl ammatory bowel disease patients. Int. Immunopharmacol. 6, 1083–1092 (2006).

Bartels LE, Jørgensen SP, Agnholt J, Kelsen J, 60

Hvas CL, Dahlerup JF: 1,25-dihydroxyvitamin D3 and dexamethasone increase interleukin-10 production in CD4+ T cells from patients with Crohn’s disease. Int. Immunopharmacol. 7, 1755–1764 (2007).

Kong J, Zhang Z, Musch MW 61 et al.: Novel role of the vitamin D receptor in maintaining the integrity of the intestinal mucosal barrier. Am. J. Physiol. Gastrointest. Liver Physiol. 294, G208–G216 (2008).

Staples JA, Ponsonby AL, Lim LL, 62

McMichael AJ: Ecologic ana lysis of some immune-related disorders, including Type 1 diabetes, in Australia: latitude, regional ultraviolet radiation, and disease prevalence. Environ. Health Perspect. 111, 518–523 (2003).

Cantorna MT, Hayes CE, DeLuca HF: 63

1,25-dihydroxycholecalciferol inhibits the progression of arthritis in murine models of human arthritis. J. Nutr. 128, 68–72 (1998).

Oelzner P, Franke S, Muller A, Hein G, 64

Stein G: Relationship between soluble markers of immune activation and bone turnover in post-menopausal women with rheumatoid arthritis. Rheumatology 38, 841–847 (1999).

Iikuni N, Nakajima A, Inoue E65 et al.: What’s in season for rheumatoid arthritis patients? Seasonal fl uctuations in disease activity. Rheumatology 46, 846–848 (2007).

Cutolo M, Otsa K, Laas K 66 et al.: Circannual vitamin D serum levels and disease activity in rheumatoid arthritis: Northern versus Southern Europe. Clin. Exp. Rheumatol. 24, 702–704 (2006).

Oelzner P, Miller A, Deschner F67 et al.: Relationship between disease activity and serum levels of vitamin D metabolites and PTH in rheumatoid arthritis. Calcif. Tissue Int. 62, 193–198 (1998).


REVIEW Armas

Kroger H, Penttila IM, Alhava EM: 68

Low serum vitamin D metabolites in women with rheumatoid arthritis. Scand. J. Rheumatol. 22, 172–177 (1993).

Merlino LA, Curtis J, Mikuls TR, Cerhan JR, 69

Criswell LA, Saag KG: Vitamin D intake is inversely associated with rheumatoid arthritis. Arthritis Rheum. 50, 72–77 (2004).

Costenbader KH, Feskanich D, Holmes M, 70

Karlson EW, Benito-Garcia E: Vitamin D intake and risks of systemic lupus erythematosus and rheumatoid arthritis in women. Ann. Rheum. Dis. 67, 530–535 (2008).

Nielen MMJ, van Schaardenburg D, 71

Lems WF et al.: Vitamin D defi ciency does not increase the risk of rheumatoid arthritis: comment on the article by Merlino et al.: Arthritis Rheum. 54, 3719–3720 (2006).

Cutolo M, Otsa K, Uprus M, Paolino S, 72

Seriolo B: Vitamin D in rheumatoid arthritis. Autoimmun. Rev. 7, 59–64 (2007).

A thorough review of the role of vitamin D

in rheumatoid arthritis.

Andjelkovic Z, Vojinovic J, Pejnovic N 73

et al.: Disease modifying and immunomodulatory effects of high dose 1 α(OH)D3 in rheumatoid arthritis patients. Clin. Exp. Rheumatol. 17, 453–456 (1999).

Cantorna MT, Mahon BD: Mounting 74

evidence for vitamin D as an environmental factor affecting autoimmune disease prevalence. Exp. Biol. Med. (Maywood) 229, 1136–1142 (2004).

Soilu-Hanninen M, Airas L, Mononen I, 75

Heikkila A, Viljanen M, Hanninen A: 25-hydroxyvitamin D levels in serum at the onset of multiple sclerosis. Mult. Scler. 11, 266–271 (2005).

Munger KL, Zhang SM, O’Reilly E 76 et al.: Vitamin D intake and incidence of multiple sclerosis. Neurology 62, 60–65 (2004).

Kragt JJ, van Amerongen BM, Killestein J77 et al.: Higher levels of 25-hydroxyvitamin D are associated with a lower incidence of multiple sclerosis only in women. Mult. Scler. 15(1), 9–15 (2009).

Munger KL, Levin LI, Hollis BW, 78

Howard NS, Ascherio A: Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 296, 2832–2838 (2006).

Cosman F, Nieves J, Komar L79 et al.: Fracture history and bone loss in patients with MS. Neurology 51, 1161–1165 (1998).

Brown SJ: The role of vitamin D in multiple 80

sclerosis. Ann. Pharmacother. 40, 1158–1161 (2006).

Wingerchuk DM, Lesaux J, Rice GPA, 81

Kremenchutzky M, Ebers GC: A pilot study of oral calcitriol (1,25(OH)

2D3) for

relapsing-remitting multiple sclerosis. J. Neurol. Neurosurg. Psychiatr. 76, 1294–1296 (2005).

Achiron A, Barak Y, Miron S82 et al.: Alfacalcidiol treatment in multiple sclerosis. Clin. Neuropharmacol. 26, 53 (2003).

Fleming JO, Hummel AL, Beinlich BR83 et al.: Vitamin D treatment of relapsing–remitting multiple sclerosis (RRMS): a MRI-based pilot study (abstract). Neurology 54(Suppl. 3), A338 (2000).

Mahon BD, Gordon SA, Cruz J, Cosman F, 84

Cantorna MT: Cytokine profi le in patients with multiple sclerosis following vitamin D supplementation. J. Neuroimmunol. 134, 128–132 (2003).

Link J, Soderstrom M, Olsson T, Hojeberg B, 85

Ljungdahl A, Link H: Increased transforming growth factor-β, interleukin-4, and interferon-γ in multiple sclerosis. Ann. Neurol. 36, 379–386 (1994).

Goldberg P, Fleming MC, Picard EH: 86

Multiple sclerosis: decreased relapse rate through dietary supplementation with calcium, magnesium and vitamin D. Med. Hypotheses 21, 193–200 (1986).

Kimball SM, Ursell MR, O’Connor P, Vieth 87

R: Safety of vitamin D3 in adults with multiple sclerosis. Am. J. Clin. Nutr. 86, 645–651 (2007).

Treatment with escalating doses of

vitamin D showed decrease in new MRI lesions.

Bischoff Ferrari HA, Orav EJ, Dawson-88

Hughes B: Effect of cholecalciferol plus calcium on falling in ambulatory older men and women: a 3-year randomized controlled trial. Arch. Intern. Med. 166, 424–430 (2006).

Mohr WB, Garland CF, Gorham ED, 89

Garland FC: The association between ultraviolet B irradiance, vitamin D status and incidence rates of Type 1 diabetes in 51 regions worldwide. Diabetologia 51, 1391–1398 (2008).

Keen H, Ekoe JM: The geography of 90

diabetes mellitus. Br. Med. Bull. 40, 359–365 (1984).

Luong KVQ, Nguyen LT, Nguyen DN: The 91

role of vitamin D in protecting Type 1 diabetes mellitus. Diabetes Metab. Res. Rev. 21, 338–346 (2005).

Sloka S, Grant M, Newhook LA: Time series 92

analysis of ultraviolet B radiation and Type 1 diabetes in Newfoundland. Pediatr. Diabetes 9, 81–86 (2008).

Littorin B, Blom P, Schölin A 93 et al.: Lower levels of plasma 25-hydroxyvitamin D among young adults at diagnosis of autoimmune Type 1 diabetes compared with control subjects: results from the nationwide Diabetes Incidence Study in Sweden (DISS). Diabetologia 49, 2847–2852 (2006).

Pozzilli P, Manfrini S, Crinò A 94 et al.; IMDIAB group: Low levels of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 in patients with newly diagnosed Type 1 diabetes. Horm. Metab. Res. 37, 680–683 (2005).

Greer RM, Rogers MA, Bowling FG 95 et al.: Australian children and adolescents with Type 1 diabetes have low vitamin D levels. Med. J. Aust. 187, 59–60 (2007).

Hyppönen E, Läärä E, Reunanen A, Järvelin 96

MR, Virtanen SM: Intake of vitamin D and risk of Type 1 diabetes: a birth-cohort study. Lancet 358, 1500–1503 (2001).

Brekke HK, Ludvigsson J: Vitamin D 97

supplementation and diabetes-related autoimmunity in the ABIS study. Pediatr. Diabetes. 8, 11–14 (2007).

Fronczak CM, Barón AE, Chase HP 98 et al.: In utero dietary exposures and risk of islet autoimmunity in children. Diabetes Care 26, 3237–3242 (2003).

Stene LC, Joner G; Norwegian Childhood 99

Diabetes Study Group: Use of cod liver oil during the fi rst year of life is associated with lower risk of childhood-onset Type 1 diabetes: a large, population-based case–control study. Am. J. Clin. Nutr. 78, 1128–1134 (2003).

Tenconi MT, Devoti G, Comelli M 100 et al.; Pavia T1DM Registry Group: Major childhood infectious diseases and other determinants associated with Type 1 diabetes: a case–control study. Acta Diabetol. 44, 14–19 (2007).

Zipitis CS, Akobeng AK: Vitamin D 101

supplementation in early childhood and risk of Type 1 diabetes: a systematic review and meta-ana lysis. Arch. Dis. Child. 93, 512–517 (2008).

Mathieu C, Waer M, Laureys J, Rutgeerts O, 102

Bouillon R: Prevention of autoimmune diabetes in NOD mice by 1,25 dihydroxyvitamin D3. Diabetologia 37, 552–558 (1994).

Mathieu C, Laureys J, Sobis H, 103

Vandeputte M, Waer M, Bouillon R: 1,25-dihydroxyvitamin D3 prevents insulitis in NOD mice. Diabetes 41, 1491–1495 (1992).

Mathieu C, Waer M, Casteels K, Laureys J, 104

Bouillon R: Prevention of Type 1 diabetes in NOD mice by nonhypercalcemic doses of a



new structural analog of 1,25-dihydroxyvitamin D3, KH1060. Endocrinology 136, 866–872 (1995).

Pedullà M, Desiderio V, Graziano A, 105

d’Aquino R, Puca A, Papaccio G: Effects of vitamin D3 analog on diabetes in the bio breeding (BB) rat. J. Cell. Biochem. 100, 808–814 (2007).

Pitocco D, Crinò A, Di Stasio E 106 et al.; on behalf of the IMDIAB group: The effects of calcitriol and nicotinamide on residual pancreatic β-cell function in patients with recent-onset Type 1 diabetes (IMDIAB XI). Diabet. Med. 23, 920–923 (2006).

Pozzilli P, Gugliemi C: Immunomodulation 107

for the prevention of SPIDDM and LADA. Ann. NY Acad. Sci. 1079, 90–98 (2006).

Abe J, Nakamura K, Takita Y 108 et al.: Prevention of immunological disorders in MRL/l mice by a new synthetic analogue of Vitamin D3: 22-oxa-1 α, 25-dihdroxyvitamin D3. J. Nutr. Sci. Vitaminol. 36, 21–31 (1990).

Lemire JM: 1,25-Dihydroxyvitamin D3 109

attenuates the expression of experimental murine lupus of MRL/lmice. Autoimmunity 123, 143–148 (1992).

Vaisberg MW, Kaneno R, Franco MF, 110

Mendes NF: Infl uence of colecalciferol (vitamin D3) on the course of experimental systemic lupus erythematosus in F1 (NZBxW) mice. J. Clin. Lab. Anal. 14, 91–96 (2000).

Barnes TC, Bucknall RC: Vitamin D 111

defi ciency in a patient with systemic lupus erythematosus. Rheumatology 43, 393–394 (2004).

Huisman AM, White KP, Algra A 112 et al.: Vitamin D levels in women with systemic lupus erythematosus and fi bromyalgia. J. Rheumatol. 28, 2535–2539 (2001).

Muller K, Kriegbaum NJ, Baslund B, 113

Sorensen OH, Thyman M, Bentzen K: Vitamin D3 metabolism in patients with rheumatic diseases: low serum levels of 25-hydroxyvitamin D3 in patients with systemic lupus erythematosus. Clin. Rheumatol. 14, 397–400 (1995).

Carvalho JF, Blank M, Kiss E, Tarr T, 114

Amital H, Shoenfeld Y: Anti-vitamin D, vitamin D in SLE. Preliminary Results. Ann. NY Acad. Sci. 1109, 550–557 (2007).

Kamen DL, Cooper GS, Bouali H, 115

Shaftman SR, Hollis BW, Gilkeson GS: Vitamin D defi ciency in systemic lupus erythematosus. Autoimmun. Rev. 5, 114–117 (2006).

Thudi A, Yin S, Wandstrat AE, Li Q-Z, 116

Olsen NJ: Vitamin D levels and disease status in Texas patients with systemic lupus erythematosus. Am. J. Med. Sci. 335, 99–104 (2008).

Cutolo M, Otsa K: Vitamin D, immunity and 117

lupus. Lupus 17, 6–10 (2008).

A thorough review of vitamin D and

systemic lupus erythematosus.

Borba VZ, Vieira JG, Kasamatsu T, 118

Radominski SC, Sato EI, Lazaretti-Castro M: Vitamin D defi ciency in patients with active systemic lupus erythematosus. Osteoporos. Int. (2008) (Epub ahead of print).

McCarty DJ, Manzi S, Medsger TA, 119

Ramseygoldman R, Laporte RE, Kwoh CK: Incidence of systemic lupus erythematosus: race and gender differences. Arthritis Rheum. 38, 1260–1270 (1995).

Ruiz-Irastorza G, Egurbide MV, Olivares N, 120

Martinez-Berriotxoa A, Aguirre C: Vitamin D defi ciency in systemic lupus erythematosus: prevalence, predictors and clinical consequences. Rheumatology 47, 920–923 (2008).

Renne J, Werfel T, Wittman M: 121

Correspondence: high frequency of vitamin D defi ciciency among patients with cutaneous lupus erythematosus. Br. J. Dermatol. 159, 485–486 (2008).

Dietrich T, Joshipura KJ, Dawson-Hughes B, 122

Bischoff-Ferrari HA: Association between serum concentrations of 25-hydroxyvitamin D3 and periodontal disease in the US population Am. J. Clin. Nutr. 80, 108–113 (2004).

Bischoff Ferrari HA, Giovannucci E, 123

Willett WC, Dietrich T, Dawson Hughes B:

Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am. J. Clin. Nutr. 84, 18–28 (2006).

Lappe JM, Travers Gustafson D, Davies KM, 124

Recker RR, Heaney RP: Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am. J. Clin. Nutr. 85, 1586–1591 (2007).

Cannell JJ, Hollis BW: Use of vitamin D in 125

clinical practice. Altern. Med. Rev. 13, 6–20 (2008).

Trang H, Cole DE, Rubin LA, Pierratos A, 126

Siu S, Vieth R: Evidence that vitamin D3 increases serum 25-hydroxyvitamin D more effi ciently than does vitamin D2. Am. J. Clin. Nutr. 68, 854–858 (1998).

Romagnoli E, Mascia ML, Cipriani C 127 et al.: Short and long-term variations in serum calciotropic hormones after a single very large dose of ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3) in the elderly. J. Clin. Endocrinol. Metab. 93, 3015–3020 (2008).

Armas LA, Hollis BW, Heaney RP: Vitamin 128

D2 is much less effective than vitamin D3 in humans. J. Clin. Endocrinol. Metab. 89, 5387–5391 (2004).

Holick MF, Biancuzzo RM, Chen TC 129 et al.: Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin D. J. Clin. Endocrinol. Metab. 93, 677–681 (2008).

Heaney RP, Davies KM, Chen TC, 130

Holick MF, Barger Lux MJ: Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am. J. Clin. Nutr. 77, 204–210 (2003).

Leventis P, Patel S: Clinical aspects of 131

vitamin D in the management of rheumatoid arthritis. Rheumatology (Oxford) 47, 1617–1621 (2008).

Hathcock JN, Shao A, Vieth R, Heaney R: 132

Risk assessment for vitamin D. Am. J. Clin. Nutr. 85, 6–18 (2007).

vitamin d, infections and immune-mediated diseases · future science group 91 vitamin d,...

Documents